Implantable system with drug-eluting cells for on-demand local drug delivery

ABSTRACT

An implantable system that includes a carrier and eukaryotic cells, which produce and release a therapeutic agent, and a stimulating element for stimulating the release of the therapeutic agent. The system can also include a sensing element for monitoring a physiological condition and triggering the stimulating element to stimulate the delivery device to release the therapeutic agent. Alternatively, the patient in which the system is implanted can activate the stimulating element to release the therapeutic agent.

This application is a Continuation-In-Part of U.S. patent applicationSer. No. 09/070,480 filed Apr. 30, 1998 abandoned, which is incorporatedby reference.

FIELD OF THE INVENTION

The present invention relates to implantable systems that includemedical devices (e.g., stents, vascular grafts, stent grafts) thatfunction as a carrier for eukaryotic cells (e.g., genetically engineeredendothelial cells). Such cells are capable of producing and releasing atherapeutic agent (e.g., tissue-type Plasminogen Activator) foron-demand localized treatment of conditions such as coronary arterydisease. The cells or the device carrying them release the therapeuticagent upon the application of a stimulus (e.g., electrical stimulus).

BACKGROUND OF THE INVENTION

Coronary Artery Disease (CAD) affects 1.5 million people in the USAannually. About 10% of these patients die within the first year and therest suffer from myocardial infarction and develop related symptoms,such as arrhythmias, CHF, and mechanical complications (e.g., aneursym,thrombus formation, pericarditis). During CAD, formnation of plaquesunder the endothelial tissue narrows the lumen of the coronary arteryand increases its resistance to blood flow, thereby reducing the O₂supply. Injury to the myocardium (i.e., the middle and thickest layer ofthe heart wall, composed of cardiac muscle) fed by the coronary arterybegins to become irreversible within 0.5-1.5 hours and is complete after6-12 hours, resulting in a condition called myocardial infarction. Ifthe ischemia due to stenosis of the coronary artery lumen could bereduced by increasing the blood circulation to the myocardium, the majorcause of most of the heart disease would be eliminated.

Current and proposed treatments for coronary artery disease typicallyfocus on pharmacological approaches and surgical intervention. Forexample, angioplasty, with and without stents, is a well known techniquefor reducing stenosis. Systemically administered drugs (e.g.,anticoagulants) are also commonly used, however, such drugs becomediluted, which can reduce their potency by the time they reach theremote site. Furthermore, systemic administration can be deleteriousbecause it can lead to complications as a result of the high dosagesrequired upon administration to allow for dilution that occurs duringtransport to the remote site. Therefore, localized delivery oftherapeutic agents is preferred. Local delivery is advantageous in thatthe effective local concentration of delivered drug is much higher thancan normally be achieved by systemic administration.

Stents have been used as delivery vehicles for therapeutic agents (i.e.,drugs). Intravascular stents are generally permanently implanted incoronary or peripheral vessels. Stent designs include those of U.S. Pat.No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S.Pat. No. 4,886,062 (Wiktor). Such designs include both metal andpolymeric stents, as well as self-expanding and balloon-expandablestents. Stents are also used to deliver a drug (e.g., antiplateletagents, anticoagulant agents, antimicrobial agents, antimetabolicagents) at the site of contact with the vasculature, as disclosed inU.S. Pat. No. 5,102,417 (Palmaz) and in International Patent ApplicationNos. WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai MedicalCenter), for example. Anticoagulant substances such as heparin andthrombolytic agents have also been incorporated into a stent, asdisclosed, for example, in U.S. Pat. No. 5,419,760 (Narciso, Jr.) andU.S. Pat. No. 5,429,634 (Narciso, Jr.). Stents have also been used todeliver viruses to the wall of a lumen for gene delivery, as disclosedin U.S. patent application Ser. No. 08/746,404, filed Nov. 8,1996(Donovan et al.).

Stents seeded with autologous endothelial cells (Dichek, et al.,Circulation, 80,1347-1353 (1989)) are disclosed as a method fordelivering recombinant protein over time to the vascular wall. Theconcentration of secreted protein produced by the endothelial cells thatis required to treat the surrounding vascular tissue can besignificantly higher than could be tolerated if delivered systemically.However, in order to be effective, it is not only necessary to release ahigh dose of the drug, but it is also necessary to achieve controlledrelease, e.g., immediately after an occlusion. Thus, it would bedesirable to control the release of such cellular components into thesurrounding tissue when needed (i.e., on demand). The present inventionprovides such a system.

Many of the following lists of patents and nonpatent documents discloseinformation related to the local delivery of therapeutic agents usingmedical devices, such as stents. Others are directed toward stentdesigns and other medical devices as well as genetically engineeredcells, for example.

SUMMARY OF THE INVENTION

The present invention provides implantable systems that include deliverydevices having a carrier and eukaryotic cells associated therewith,optionally within a containment vehicle. Such cells are capable ofproducing at least one therapeutic agent (i.e., drug), which is releasedfrom the delivery device upon the application of a stimulus (e.g.,electrical stimulus) for on-demand (i.e., when needed) localizedtreatment of conditions such as coronary artery disease or cerebral isvascular occlusion, for example. The cells are referred to herein as“drug-eluting” cells.

Release of the therapeutic agent from the delivery device is stimulatedby a variety of methods, including electrical stimulation, which can beused to create an electrical field or mechanical stimulus, for example.This can be accomplished by direct action on the cells, such as bystimulating the cellular membrane to release the cellular productscontained therein. Alternatively, this can be accomplished by activatingthe cellular products such that upon release they will function astherapeutic agents. This can also be accomplished by stimulating amicroscopic containment vehicle that contains the cells, such as bystimulating a synthetic membrane of the containment vehicle, to releasethe cells and/or their cellular products.

Thus, an object of the present invention is to provide a system andmethod for the treatment (including prevention) of coronary arterydisease, for example, by producing and delivering locally a therapeuticagent, such as an anticoagulant. Significantly, the local dosage can becontrolled and provided on demand without worrying about the systemiceffects. Furthermore, the local dosage can be administered prior tosignificant physiological damage occurs to the patient.

In a preferred embodiment, the present invention provides an implantablesystem that includes: a delivery device comprising a carrier forcarrying eukaryotic cells that produce at least one therapeutic agent; astimulating element for stimulating the release of the therapeutic agentfrom the delivery device; and a sensing element for monitoring at leastone physiological property of a patient in which the system is implantedand communicating with the stimulating element to stimulate the releaseof the therapeutic agent from the delivery device.

In another embodiment, an implantable system includes a delivery devicecomprising an intraluminal stent, which includes a lumen-wall contactingsurface, a lumen-exposed surface, a first polymer composition coveringat least a portion of the stent (preferably, at least a portion of thelumen-exposed and the lumen-wall contacting surfaces), and endothelialcells associated with the first polymer composition covering, whereinthe endothelial cells produce at least one therapeutic agent. Theimplantable system further includes an electrical stimulating elementfor stimulating the release of the therapeutic agent from the deliverydevice, and a sensing element for monitoring at least one physiologicalproperty of a patient in which the system is implanted and communicatingwith the electrical stimulating element to stimulate the release of thetherapeutic agent from the delivery device.

The present invention also provides a method of local delivery (asopposed to systemic delivery) of a therapeutic agent. The methodinvolves simply implanting an implantable system described above. Onceimplanted into a patient, the therapeutic agent is released from thedelivery device when the sensing element detects a predetermined levelof a physiological property (e.g., a certain pH or level of blood flowor blood gases) and communicating with the stimulating element totrigger the release.

A method of making an implantable system for local delivery of atherapeutic agent is also included within the scope of the presentinvention. The method includes: providing a delivery device comprising acarrier and eukaryotic cells associated therewith that produce at leastone therapeutic agent; providing a stimulating element for stimulatingthe release of the therapeutic agent from the delivery device; providinga sensing element for monitoring at least one physiological property ofa patient in which the system is implanted; and connecting thestimulating element and sensing element such that they communicate witheach other to stimulate the release of the therapeutic agent from thedelivery device when implanted in the body of a patient and the sensingelement detects a predetermined level of a physiological property.Preferably, the step of providing a delivery device includes: providinga carrier; isolating eukaryotic cells from a patient; culturing theeukaryotic cells; delivering nucleic acid of a desired therapeutic agentto the eukaryotic cells to form genetically engineered eukaryotic cells;and contacting the carrier with the genetically engineered eukaryoticcells.

In an alternative embodiment, the present invention provides implantablesystems as described above without the sensing element. In such systems,the patient in which the system is implanted activates the stimulatingelement when desired (i.e., on demand). Typically, this occurs when thepatient detects a change in a physiological condition (e.g., angina) andcommunicates with the electrical stimulating element to trigger releaseof the therapeutic agent. The patient can communicate with theelectrical stimulating element to activate it using radio frequency,infrared, or acoustic pulses.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a method of making and implanting adrug-loaded stent of the present invention.

FIG. 2 is an illustration of an implantable system according to thepresent invention that includes the use of an RF signal to communicateand generate an electrical current in a coiled stent. Inset FIG. 2A is adiagramatic representation of a circuit in a coiled stent forelectrically stimulating the cells in association with the stent.

FIG. 3 is an elevational view of a preferred balloon catheter with stentincluding fibrin and drug-eluting cells according to the presentinvention.

FIG. 4 illustrates a method of loading a stent with drug-eluting cells.

FIG. 5 shows a circuit for an implantable medical device according tothe present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides implantable systems for the treatment(including prevention) of a variety of disorders, such as, coronaryartery disease, which can be manifested by stenosis, myocardialinfarction, aneurysm, angina, and/or atherosclerosis, orcerebro-vascular occlusion, which can result in a stroke, for example.The implantable systems of the present invention include a deliverydevice comprising a carrier (e.g., stents, vascular grafts, stentgrafts) and eukaryotic cells (e.g., genetically engineered endothelialcells), which can optionally be enclosed within containment vehicles.Such cells are capable of producing one or more therapeutic agents(e.g., proteins and other cellular products) that have a preventative,therapeutic, or disease-treating effect on surrounding tissue.

The therapeutic agents are released from the delivery device upon theapplication of a stimulus (e.g., electrical stimulus). This can occur asa result of the stimulus acting directly on the cells to cause them toproduce, activate, and/or release the therapeutic agents. Alternatively,this can occur as a result of the stimulus acting on the optionalcontainment vehicles within the delivery device, for example.Significantly, the local dosage can be controlled and provided on demandwithout worrying about the systemic effects, and before significantdamage occurs to the heart muscle, for example.

Referring to FIG. 1, in one preferred embodiment, endothelial cells 12are obtained from a patient 10 and grown in cell culture 14. Duringproliferation in cell culture 14, cells are infected with a geneticallyengineered retrovirus which integrates the gene for the drug to belocally delivered into the chromosomes of the endothelial cells. Acylindrical coil shaped stent 18 is produced out of a conductive metaland coated with an insulative material, such as an organic polymer,except at its ends, and with genetically engineered endothelial cells19. The stent 18 coated with endothelial cells is introduced into thepatient 10. Typically, the coated stent is implanted into theappropriate coronary artery during a catheterization procedure, into theright or left coronary artery depending on the pathophysiology.

Referring to FIG. 2, a preferred embodiment of the implantable system 20of the present invention includes, in addition to the coated stent 18, astimulation device 22 that includes, for example, an implantablegenerator, which can be implanted in the left pectoralis major area, atraditional pacemaker implant site, along with an isolated lead orantenna 24 traveling to the right ventricle via the subclavian vein,superior vena cava, and tricuspid valve, a traditional pacemaker leadplacement technique. The stimulation device 22 can monitor the patient(using a sensing element incorporated within the device 22), if desired,and trigger the stent (using a stimulating element incorporated withindevice 22) with engineered endothelial cells to release the cellularproduct(s). Typically, as is shown in this embodiment, the stimulationdevice is remote from the delivery device.

Alternatively, the patient can control the stimulation device and causethe stent to release the therapeutic agent(s) upon sensing aphysiological change (e.g., angina) using a patient activator tocommunicate with the stimulating element. In this embodiment, thestimulation device does not need a sensing element; rather, the patientacts as the sensor to detect an undesirable or a change in aphysiological condition. Such patient activators can involve the use ofradio frequency, infrared, acoustic pulsed, or magnetic means. Forexample, upon experiencing angina (i.e., chest pain), a patient can holda hand-held device in place over the implant site of the stimulatingelement (e.g., an implantable pulse generator) to communicate with itand activate it to stimulate the remote endothelial cells.

The sensing element can be in the form of electrocardiogram (ECG) formonitoring changes in the circulatory system, such as a reduction ofblood flow in the coronary sinus, for example. A sudden change in ECGmorphology such as ST segment elevation is usually due to the onset ofischemia caused by a decrease in flow due to an occlusion resulting fromthe rupture of an unstable plaque (i.e., a blood clot). Other sensors,such as blood gas sensors, for example, can alternatively oradditionally be used to detect changes in a patient's coronarycirculatory system. Once the onset of ischemia is detected, animplantable pulse generator (IPG), for example, will trigger thedelivery device (preferably, by stimulating the endothelial cells) torelease one or more cellular products (e.g., tissue-type PlasminogenActivator or t-PA) to dissolve the clot and prevent the infarction fromtaking place.

In one preferred embodiment, as illustrated by FIG. 2, when it is timeto reduce the coagulation in a coronary artery (as determined by asensing element in an implantable stimulation device 22 or by a patientexperiencing angina), a radio frequency signal 26 is sent to the coilformed by the stent 18. Because the ends of the stent 18 are notinsulated, electromotive force (EMF) generated by the RF signal isdelivered to the drug-eluting cells. Upon that event, the cells, e.g.,genetically engineered endothelial cells, can be stimulated to releasetheir stores of thrombolytic agents, such as tissue-type plasminogenactivator, immediately.

Placement of genetically engineered endothelial cells, for example,upstream in the coronary artery will allow the secretion of varioustherapeutic agents (i.e., drugs) into the lumen, and the blood willcarry them through the rest of the circulatory system. Although thiseventually results in more of a systemic delivery, the administration ofthe therapeutic agent is initiated as local delivery at the site of thedelivery device. Release of tissue-type plasminogen activator (t-PA) byengineered endothelial cells in a coronary artery would allow a potentdose of the drug to be delivered locally while avoiding dilution, andpotential toxicity as in the case of systemic administration of the samedrug. Ideally, this system will dissolve blood clots, for example, assoon as they form through the localized delivery of potent quantities oft-PA, for example, upstream from the site of thrombus formation.

Drug-Eluting Cells

Cells suitable for use in the present invention include a wide varietyof eukaryotic cells that produce therapeutic agents, or can begenetically engineered to produce therapeutic agents. Ideally, suchcells are also able to secrete these agents, particularly upon theapplication of a stimulus, such as an electrical stimulus. Suitablecells for use in the present invention typically include mesenchymal ormesodermal cells, including, but not limited to endothelial cells andfibroblasts, whether they are autologous or allogeneic, geneticallyengineered or nonengineered. Mixtures of such cells can also be used.Endothelial cells are particularly suitable for use in the presentinvention because they line the walls of the blood vessels. They arealso particularly suitable for use in the present invention because theyare capable of secreting vasodilatory, thrombolytic, or angiogenicfactors, which can facilitate recovery of ischemic myocardium.

Endothelial cells and fibroblasts are preferred because they have beenshown to be suitable for use in ex vivo gene transfer. Ex vivo genetransfer (also referred to herein as ex vivo gene therapy) is a processby which cells are removed from the body using well known techniques,genetically manipulated, usually through transduction or transfection ofnucleic acid into the cells in vitro, and then returned to the body fortherapeutic purposes. This contrasts with in vivo gene therapy, where agene transfer vector is administered to the patient resulting in genetictransfer into cells and tissues in the intact patient. Ex vivotechniques are well known to one of skill in the art.

Ex vivo gene therapy is an effective approach because the target cellsto be used in the procedure can be manipulated as needed to optimizegene transfer efficiency and thus the effectiveness of the overallprocedure. However, the ex vivo approach can only be utilized for thosecell types which can be readily retrieved from the body, cultured exvivo, and then returned to the body. Such cells include blood and marrowcells, liver hepatocytes, skin fibroblasts, muscle myoblasts, andvascular endothelial cells. Thus, endothelial cells and fibroblasts,which can be efficiently infected by retroviral vectors in vitro, andthen transplanted back into the host to achieve gene transfer in vivo,are particularly preferred for use in the present invention.

Autologous endothelial cells are particularly desirable. Vascularendothelial cells have been removed from a patient and transduced exvivo with a retroviral vector designed for expression of β-galactosidaseas a reporter gene, as disclosed in Nabel et al., Science, 244,1342-1344 (1989). Such genetically engineered cells can be reintroducedinto a patient. For example, Nabel et al. showed that endothelial cellsengineered to express β-galactosidase could be introduced into anoccluded vascular site using a balloon catheter, after which thepresence of engrafted endothelial cells could be detected by stainingfor β-galactosidase activity.

In one embodiment of the present invention, endothelial cells areobtained from a patient and grown in cell culture. During proliferationin cell culture, they are infected with a genetically engineeredretrovirus which integrates the gene for the drug to be locallydelivered into the chromosomes of the endothelial cells. This can beaccomplished, for example, according to the teachings of U.S. Pat. No.5,674,722 (Mulligan et al.) and Dichek et al., Mol. Biol. Med., 8,257-266 (1991). For the treatment of coronary artery disease (CAD),candidate genes include the gene encoding wild-type tissue plasminogenactivator and the gene encoding protein C, for example. The isolationand characterization of the human t-PA structural gene is disclosed inFisher et al., J. Biol. Chem., 260, 11223-11230 (1985).

Activated Protein C degrades the coagulation factors which areresponsible for the formation of life threatening clots in the coronaryarteries. However, protein C requires the presence of Ca⁺⁺ (calcium ion)for its own activation, which is controlled in the cells by ion gateswhich, in turn, are under the control of the voltages across the cellmembrane. Thus, electrical stimulation of the cells can activate proteinC. For example, endothelial cells may be depolarized, thereby alteringthe ion concentrations within the cells. Although the inventors do notwish to be bound by theory, it is believed that changing ionconcentration, such as calcium ion concentration, may trigger secretionof certain cellular products, such as t-PA. Alternatively, calcium ionscan activate protein C, which can start the cascade for the reduction ofcoagulation factors and prevent the formation of clots.

There are a wide variety of methods that can be used to deliver nucleicacid to the eukaryotic cells if they are to be modified to secrete adesired agent. These are well known to one of skill in the art. Thedesired nucleic acid can be inserted into an appropriate deliveryvehicle, such as, for example, an expression plasmid, cosmid, YACvector, and the like. There are a number of viruses, live or inactive,including recombinant viruses, that can also be used. A retrovirus canbe genetically modified to deliver any of a variety of genes. Adenovirushas been used in a variety of experiments to deliver nucleic acidcapable of directing and expressing protein in a cell. These include,but are not limited to, superoxide dismutase, tissue plasminogenactivator, and interleukin-10.

Exemplary nucleic acid that would function as nucleic acid forincorporation into the cells include, but are not limited to, nucleicacid operably encoding a protein, polypeptide, or peptide to deliver atherapeutic effect to a cell. The nucleic acid can include an entiregene or a portion of a gene. Exemplary genes include, but are notlimited to, the active form of the nitric oxide synthase (a protein thatis known to relax blood vessels and prevent clot formation), andprostaglandin H synthase (to restore an endogenous inhibitor of plateletaggregation and vasoconstriction following injury to endothelium).

There are a variety of disorders that can be treated using the systemsand devices of this invention. Examples of these disorders include, butare not limited to, damage associated with myocardial infarction oraneurysms (targeting fibroblast growth factor or transforming growthfactor , and protease, respectively), atherosclerosis (targeting highdensity lipoprotein), and hypercoagulable states (targetingtissue-plasminogen activator).

The gene sequence of the nucleic acid delivered by the virus, includingnucleic acid encoding proteins, polypeptide or peptide is available froma variety of sources including GenBank (Los Alamos NationalLaboratories, Los Alamos, N.Mex.), EMBL databases (Heidelberg, Germany),and the University of Wisconsin Biotechnology Center, (Madison, Wis.),published journals, patents and patent publications. All of thesesources are resources readily accessible to those of ordinary skill inthe art. The gene sequence can be obtained from cells containing thenucleic acid fragment (generally, DNA) when a gene sequence is known.The nucleic acid can be obtained either by restriction endonucleasedigestion and isolation of a gene fragment, or by polymerase chainreaction (PCR) using oligonucleotides as primers either to amplify cDNAcopies of mRNA from cells expressing the gene of interest or to amplifycDNA copies of a gene from gene expression libraries that arecommerically available. Oligonucleotides or shorter DNA fragments can beprepared by known nucleic acid synthesis techniques and from commercialsuppliers of custom oligonucleotides such as Amitof Biotech Inc.(Boston, Mass.), or the like. Those skilled in the art will recognizethat there are a variety of commercial kits available to obtain cDNAfrom mRNA (including, but not limited to Stratagene, La Jolla, Calif.and Invitrogen, San Diego, Calif.). Similarly, there are a variety ofcommercial gene expression libraries available to those skilled in theart including libraries available form Stratagene, and the like. Generalmethods for cloning, polymerase chain reaction and vector assembly areavailable from Sambrook et al. eds. (Molecular Cloning: A LaboratoryManual, 1989 Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y.) and Innis, et al. eds. (PCR Strategies, 1995, Academic Press, NewYork, N.Y.).

Depending on the maximum genome size that a particular viral genome canaccommodate or that can be associated with a virus particle, the virusdelivering nucleic acid to the cell can include nucleic acid encodingone or more proteins, polypeptides, or peptides. Oligonucleotides can bedelivered by virus through the incorporation of oligonucleotides withinthe virus or associated with the outer surface of the virus usingmethods well known to one of skill in the art.

Therapeutic agents (i.e., drugs) that can be produced, stored, andsecreted by eukaryotic cells, particularly genetically engineeredendothelial cells, include, but are not limited to, anticoagulantagents, antiplatelet agents, antifibrinolytic agents, angiogenesisfactors, etc. Specific examples include activated protein C, tissueplasminogen activator, prostacyclin, and vascular endothelial growthfactor (VEGF). Such cells are referred to herein as “drug-eluting”cells.

The drug-eluting cells can be coated directly on the carrier of thedelivery device or they can be incorporated into the carrier, as in apolymer film (i.e., sheeting) or coating on a stent. They can also beincluded within a microscopic containment vehicle that can be stimulatedto release the cells and/or their cellular products. The microscopiccontainment vehicle can be coated on the carrier or incorporated intothe carrier, as in a polymer film or coating on a stent. The cells canbe induced to produce, activate, and/or release their cellular products(including one or more therapeutic agents) by an external stimulationdevice. This can occur as a result of destruction of the cellularmembrane, for example. Alternatively, cells can constitutively releaselow levels of one or more therapeutic agents all the time. These cellswould be preferentially placed in a containment vehicle, which wouldthen be induced to release the therapeutic agent by an externalstimulation device.

Delivery Devices

The drug-eluting cells can be carried by a variety of carriers for usein the delivery devices of the present invention. For example,intravascular stents and vascular grafts have been seeded withendothelial cells expressing recombinant t-PA, as disclosed in Dichek etal., Circulation, 8, 1347-1353 (1989) and Dichek et al., Circulation,93, 301-309 (1996). In addition to stents and vascular grafts or stentgrafts, suitable carriers for use in delivery devices of the presentinvention include, but are not limited to, synthetic patches, infusionsleeves, medical electrical leads and electrodes, and indwellingcatheters.

Although any of these devices can be used as carriers for thedrug-eluting cells, the following description focuses on stents. Whetherthe carrier is a stent or other medical device, the drug-eluting cellscan be directly coated onto the carrier, incorporated into or onto apolymeric coating or film on the carrier, incorporated into microscopiccontainment vehicles and coated directly on the carrier or incorporatedinto or onto a polymeric coating or film on the carrier. As used herein,a “delivery device” includes the carrier (e.g., stent), cells thatproduce one or more therapeutic agents, and optional containmentvehicles, as well as other optional therapeutic materials.

The term “stent” refers to any device capable of being placed intocontact with a portion of a wall of a lumen. It includes classicalstents used in intravascular applications, as well as any prosthesisthat may be inserted and held where desired in a lumen. Such prosthesesinclude single- or multi-filar braided mesh designs, metallic malleabledesigns, and others, as disclosed, for example, in International PatentApplication No. WO 91/12779 (Medtronic, Inc.).

Typically, the stent has a lumen wall-contacting surface and alumen-exposed surface. Where the stent is shaped generally as atube-like structure, including a discontinuous tube or a ring-likestructure, the lumen-wall contacting surface is the outside surface ofthe tube and the lumen-exposed surface is the inner surface of the tube.The stent can include polymeric elements, metallic elements, filametaryelements, or combinations thereof. It can be coated with fibronectin orother extracellular matrix for adhering the cells to the stent.Preferably, the stent includes a fibrin or collagen coating or film orother natural or synthetic polymeric coating or film for holding thecells in place.

A deformable metal wire stent useful as a stent framework to support thecells of this invention is disclosed in U.S. Pat. No. 4,886,062(Wiktor). Other metallic stents useful in this invention include thoseof U.S. Pat. No. 4,733,655 (Palmaz) and U.S. Pat. No. 4,800,882(Gianturco). FIG. 3 provides an elevational view of a preferred stent 30of this invention. In one preferred embodiment, the stent comprises astent framework 32 with a polymer film 34 (preferably, a fibrin film)extending circumferentially around at least a portion of the lumen-wallcontacting surface of the stent and/or the lumen-exposed surface of thestent and preferably extending over substantially all of the lumen-wallcontacting and lumen-exposed surfaces. A balloon 36 is positioned inFIG. 3 adjacent the lumen-exposed surface of the stent to facilitatedelivery of the stent. Polymeric stents can also be used in thisinvention, whether they be nonbioabsorbable or bioabsorbable in part, ortotal.

The drug-eluting cells can be coated directly on the stent or they canbe incorporated into a polymer film (i.e., sheeting) or coating. Thestents of this invention preferably include a first polymer compositioncomprising fibrin or other polymer to provide containment for thedrug-eluting cells. The first polymer composition of this invention canbe prepared from a homopolymer, a copolymer (i.e., a polymer of two ormore different monomers), or a composition (e.g., a blend) comprisingfibrin with one or more polymers or copolymers, for example. Thecomposition preferably forms a viscoelastic, tear-resistant,biocompatible polymer. The term “viscoelastic” refers to the prescribed“memory” characteristics of a molecule that allow the molecule torespond to stress as if the molecule was a combination of elastic solidsand viscous fluids. The term “tear resistent” indicates that when thepolymer is exposed to expansion stress, the material does notsubstantially tear. Tearing refers to the propagation of a nick or cutin the material while under stress. When the stent of this invention isexpanded on a balloon, the polymer is able to expand to accommodate theballoon expansion. The term “biocompatible” is used herein to refer to amaterial that does not have toxic or injurious effects on biologicalsystems.

Preferably, the first polymer composition minimizes or does notexacerbate irritation to the lumen wall when the stent is in position.The first polymer composition is preferably nonthrombogenic when appliedalone or alternatively when used with anti-thrombogenic agents such asheparin, and the like, or with anti-inflammatory agents such ascyclosporins, and the like. The first polymer composition is alsopreferably a biostable or a bioabsorbable polymer depending on thedesired rate of release or the desired degree of polymer stability.

The stents of this invention can be coated with fibrin, for example, byapplication of a fibrinogen solution and a solution of afibrinogen-coagulating protein or by attachment of a fibrin preform orsleeve such as an encircling film of fibrin, including the film providedin U.S. Pat. No. 4,548,736 (Muller). As described in U.S. Pat. No.4,548,736 (Muller) and U.S. Pat. No. 5,510,077 (Dinh et al.), fibrin isclotted by contacting fibrinogen with a fibrinogen-coagulating proteinsuch as thrombin. The fibrinogen is preferably used in solution with aconcentration of about 10 to about 50 mg/ml with a pH of about 5.89 toabout 9.0 and with an ionic strength of about 0.05 to about 0.45. Thefibrinogen solution typically contains proteins and enzymes such asalbumin, fibronectin, Factor XIII, plasminogen, antiplasmin, andAntithrombin III. The thrombin solution added to make the fibrin istypically at a concentration of up to about 120 NIH units/ml with apreferred concentration of calcium ions between about 0.02 M and 0.2 M.Also preferably, the fibrinogen and thrombin used to make fibrin in thepresent invention are from the same animal or human species as that inwhich the stent of the present invention will be implanted to avoidcross-species immune reactions. The resulting fibrin can also besubjected to heat treatment at about 150° C., for about 2 hours toreduce or eliminate antigenicity.

The fibrin, or other polymer, can be in the form of a film produced bycasting the combined fibrinogen and thrombin in a film and removingmoisture from the film osmotically through a moisture permeablemembrane. Alternatively, a substrate can be contacted with a fibrinogensolution and with a thrombin solution resulting in a fibrin film formedby polymerization of fibrinogen on the surface of the device. Multiplelayers of fibrin applied by this method can provide a fibrin film in avariety of thicknesses. In another method, the fibrin can be firstclotted and then ground into a powder that is mixed with water andstamped into a desired shape in a heated mold. These methods can be usedwith fibrin monomers or with combinations of monomers to form the firstpolymer composition of this invention. Those skilled in the art willrecognize that the methods for forming the first polymer composition canbe modified to include other polymers, as contemplated in thisinvention, without undue experimentation.

The first polymer compositions of this invention can include one or moreother synthetic or natural polymers. Suitable polymers include thosethat are compatible with the cells and therapeutic agents. Theseinclude, but are not limited to, fibrins, collagens, alginates,polylactic acids, polyglycolic acids, celluloses, hyaluronic acids,polyurethanes, silicones, polycarbonates, mixtures or copolymersthereof, and a wide variety of other polymers typically disclosed asbeing useful in implantable medical devices. An example of a copolymerwith improved structural strength and improved biological performance isa fibrin and polyurethane copolymer, as disclosed in U.S. Pat. No.5,510,077 (Dinh et al.), or a fibrin alginate copolymer. Because fibrinis more readily degraded in the body than polyurethane, polyurethane canbe used to regulate degradation of the fibrin covering the stent and toslow release of the cellular products from the stent.

Heparin, or other anticoagulants, such as polyethylene oxide, hirudin,and tissue plasminogen activator, can be incorporated into the stentprior to implantation in an amount effective to prevent or limitthrombosis. A heparin immersion procedure can be used to incorporate theheparin. A heparin solution can alternatively be added at the time thatcells are loaded onto the stent. Heparin can also be incorporated intothe polymer matrix before it has completely polymerized. For example,powdered heparin can be dusted onto the stent during the polymerizationprocess and additional thrombin and fibrinogen can then be applied as acoating over the heparin.

The shape of the polymer film or coating can be modified based on themethods used to cover the stent. It can be spray coated onto the stentor a film can be molded over the stent framework. The first polymercomposition of this invention can cover both the lumen wall contactingsurface and the lumen-exposed surface of the stent.

Alternatively, a porous polymeric sheet material can be used into whichfibrin is incorporated. The sheet could be prepared from polyurethane,for example, by dissolving a polyether urethane in an organic solventsuch as 1-methyl-2-pyrrolidone; mixing into the resulting polyurethanesolution a crystalline particulate material like salt or sugar that isnot soluble in the solvent; casting the solution with particulatematerial into a thin film; and then applying a second solvent, such aswater, to dissolve and remove the particulate material, thereby leavinga porous sheet. The porous sheet could then be placed into a fibrinogensolution in order to fill the pores with fibrinogen followed byapplication of a solution of thrombin and fibrinogen to the surface ofthe sheet to establish a fibrin matrix that occupies both the surface ofthe sheet and the pores of the sheet. Preferably, a vacuum would bepulled on the sheet to insure that the fibrinogen applied to the sheetis received into the pores.

The stent framework can also be positioned within a mold and thecompounds forming the first polymer composition incorporated into themold. The first polymer composition forming a sheet or sleeve can beprepared in an extended shape and then compressed or dehydrated into afinal shape to fit over the stent. In this way, when the stent isexpanded in place to fit the walls of a lumen, the first polymercomposition can be readily expanded without tearing or introducingirregularities into the sleeve and/or the coating.

The stent can be loaded with drug-eluting cells by mixing the monomersolution of the first polymer composition with cells or by directlyapplying the cells to the polymerized composition. In a firstembodiment, the stent is loaded with cells at the time of formation ofthe first polymer composition. FIG. 4 provides an example where a stentis formed over a balloon and introduced into a mold cavity to receive asolution sufficient to form the first polymer composition and includingcells to be incorporated into the first polymer coating. In FIG. 4, thestent framework 42 is positioned over the balloon 46 and introduced intoa mold 48. A monomer solution capable of forming a first polymercomposition is introduced into the mold along with the drug-elutingcells. Once the polymer is formed over the stent framework 42, the stentis released from the mold. The drug-eluting cells can also be includedin a monomer solution as a spray or liquid coating to be applied to thestent framework.

Alternatively, the drug-eluting cells can be added to the polymer coatedstent either at the time of stent manufacture or by the physician, priorto stent implantation. Where the first polymer composition is capable ofdehydration and rehydration, the fibrin coated stent can be supplied ina sterile, dehydrated form and cells can be loaded onto the stent byrehydration of the first polymer composition positioned on the stentframework by immersing, wicking, or spraying a liquid suspension (suchas a balanced salt solution, including HBSS or a tissue culture media,and the like) containing the cells onto the stent prior to stentimplantation. The liquid used to deliver cells to the first polymercoating should support the stability of the cells and should include pHbuffered solutions, stabilizers such as albumin, glycerol, or the like,in a form that is biocompatible and preferably nonimmunogenic.

In one embodiment, a dehydrated first polymer covered stent can berehydrated in a solution of calcium chloride and sodium alginatecontaining the drug-eluting cells. The solution can be sprayed onto thestent, for example. A layer of calcium alginate then precipitates ontothe surface of the stent with the cells. Alternatively, a dehydratedfirst polymer covered stent can be rehydrated in a solution of sodiumalginate containing the drug-eluting cells, and then a layer of calciumalginate is sprayed or otherwise coated over the first polymer coveringand cells. Where the cells are incorporated into a polymer solution forspray application or air pump applications, the polymer should be ofsufficiently low viscosity to facilitate the application of the solutionto the stent.

In another embodiment of the stents of this invention, a second polymercomposition can be added over the first polymer composition following,or at the time of, cell loading. Preferably, the second polymercomposition is biodegradable and the second polymer composition coats atleast a portion of the first polymer composition and cells. For example,after the cells are loaded onto a stent having a first polymercomposition coated thereon, the stent can be sprayed with or immersed ina solution to form a coating of a biodegradable polymer such aspolylactic acid or methylcellulose, with or without heparin, or anothercoagulation inhibitory or anti-inflammatory compound. Advantageously,the second covering of polymer provides even greater sustained releasecapabilities and prevents loss of cells from the coated or covered stentduring transit through the body to the target site on the body lumen.Suitable polymers for use in the second polymer composition include, butare not limited to, those listed above for the first polymercomposition, and combinations thereof, and a wide variety of otherstypically disclosed as being useful in implantable medical devices.

One or more surfaces of the stent can be coated with one or moreadditional coatings of a polymer that is the same or different from thesecond polymer composition. Additional polymer coatings on thelumen-exposed surface are used to prevent release of the cells from thelumen-exposed surface of the stent when the stent is positioned in thebody. This embodiment is particularly useful where the stent is used inthe blood vasculature and in particular where the stent is used in thecoronary artery.

The drug-eluting cells can also be included within a microscopiccontainment vehicle that can be stimulated to release the cells and/ortheir cellular products. This microscopic containment vehicle can becoated onto the delivery device directly or into or onto a polymercoating or film. The drug-eluting cells are enclosed within such avehicle. Upon stimulation of the containment vehicle, the cells and/orcellular products (e.g., therapeutic agents) are released from thecontainment vehicle. Such containment vehicles are particularlydesirable for cells that continuously produce and release thetherapeutic agent. Thus, instead of stimulating the cells themselves,the containment vehicle is stimulated to release the cells and/ortherapeutic agents. Stimulation of the containment vehicles can beaccomplished using a variety of techniques.

Examples of microscopic containment vehicles include, but are notlimited to, those described in International Patent Application Nos. WO96/28841 (Ohman) and WO 96/34417 (Smela et al.), and in Smela et al.,Science, 268, 1735-1738 (1995), which disclose micromachined structuresand microactuators. In one example, such micromachined structuresinclude conducting bilayers made of a layer of polymer and a layer ofgold that are used as hinges to connect rigid plates to each other andto a silicon substrate. The bending of the hinges is electricallycontrolled and reversible, allowing precise three-dimensionalpositioning of the plates. The use of differential adhesion allows thestructures to be released from the silicon substrate. Thus, complexshapes can be formed, such as cubes, of micrometer size that could beused to contain drug-eluting cells and their cellular products inassociation with a delivery device such as a stent, until they areneeded for therapeutic or preventative treatment.

Microscopic containment vehicles can also include micropumps,reservoirs, with piezoelectric valves. The body of the pump andreservoir can be made of a polymeric material while the valves contain apiezoelectric material, which allows opening and closing of the valvesand pumping movement by electrical stimulation. The reservoirs containthe drug-eluting cells and their cellular products. Upon stimulation ofthe piezoelectric material, the valve is opened to release the cellsand/or cellular products. Implantable piezoelectric pumps are known(see, for example, U.S. Pat. No. 4,944,659 (Labbe et al.)) and can bemodified by one of skill in the art to form containment vehicles for thepresent invention.

The stents of this invention can be provided in a sterile, dehydratedform, in a hydrated form with cells (shipped frozen or on ice) or as afirst polymer covered stent supplied with the necessary materials tofacilitate cells loading and further coating or covering of the stent asneeded. Therefore, this invention also relates to a kit comprising astent with a first polymer composition comprising fibrin, bufferssuitable for rehydrating the stent and loading the cells and a containerto facilitate sterile loading of the stent. Optionally, the kit caninclude further coatings or coverings to be applied over the firstpolymer composition. In a preferred embodiment, the kit includes: astent comprising a lumen-wall contacting surface, a lumen-exposedsurface, and a first polymer composition comprising fibrin covering atleast a portion of the stent; a cell-loading composition to be appliedto the stent; and a container to house the stent and the compositionduring application of the cell-loading composition.

Stimulatinq and Sensing Elements

Systems of the present invention include a second implantable device(i.e., a stimulation device) that includes a stimulating element, suchas an implantable pulse generator (IPG) similar in many respects topacemakers and defibrillators known in the art, for example, which ispreferably in contact with a sensing element. This device monitors thepatient to detect when a stimulus needs to be sent to the cells totrigger release of one or more therapeutic agents. This monitoring canbe in the form of an electrocardiogram (ECG), for example, to detect anST segment elevation or a reduction of blood flow in the coronary sinus.Once the onset of ischemia is detected, the stimulating element willtrigger the release of cellular products. For example, when a blood clotis formed that reduces blood flow, an abnormal ECG is produced, whichcauses an IPG, for example, to trigger a stent to stimulate endothelialcells to release t-PA, which travels to the blood clot and dissolves it,thereby preventing myocardial infarction.

Cellular products can be released upon the action of a stimulus directlyon the cells, particularly the cellular membrane, or on the microscopiccontainment vehicle in which the cells are optionally located. Thecellular products, particularly the therapeutic agents, are thendistributed to the desired site through a washing action of the deliverydevice with body fluids. Following stimulation of the cells orcontainment vehicle, cellular products can also be released by erosionor bioabsorption of the coated surfaces of the stent, for example, bydissolution of fibrin or hydrolysis resulting in crosslink cleavage andconcomitant release of the physically entrapped cells.

The stimulation device can provide electrical stimulation, mechanicalstimulation, acoustic stimulation, thermal stimulation, chemicalstimulation, or combinations thereof, to the eukaryotic cells and/or thecontainment vehicles, for example. One of skill in the art willrecognize that a variety of means of stimulation can be used toelectrically, mechanically, acoustically, and/or chemically stimulatethe cells and/or the containment vehicles. The following are presentedas examples only and do not limit the specific mechanisms or devices bywhich the stimulation can occur.

Typically, electrical stimulation causes ions to flow through cellsmaking their membranes permeable. If sufficient stimulation is applied,then large pores are created on the cellular membrane, which aresufficient for the cellular product to pass through. Electricalstimulation can occur as described herein with reference to FIG. 2.

Mechanical stimulation can be applied by twisting the cellular membranesof the cells, for example. This causes a shear force on the cells andelongates them. Surface area is not changed but the enclosed volume isdecreased so the intracellular pressure increases, causing the contentsof the cells to leak out. Alternatively, mechanical stimulation can beaccomplished through the use of a piezoelectric material (e.g., apiezoelectric crystal) on the surface of the carrier of the deliverydevice. When an electrical pulse is applied to the crystal, it changessize (e.g., longer or shorter), which can stretch or compress thecarrier, and hence cause pressure on the cells. Acoustic stimulation isa similar to mechanical stimulation, but the pressure is appliedrepetitively by sound waves.

Thermal stimulation involves applying heat to the cells, which can causethem to release their cellular products. This can be accomplished by theuse of resistive elements inside the carrier of the delivery device.When electrical current is applied, the resistive element applies heatto the cells.

Chemical stimulation involves releasing a compound (e.g., a ligand) intothe blood stream that acts via a lock and key mechanism to interact withthe cells. For example, a ligand can be released from the stimulationdevice and when it reaches the cells in the delivery device, it canattach to an appropriate receptor on the cells and trigger eventsleading to the release of the therapeutic agent.

Although current implantable pulse generators (IPGs) are designed tostimulate cardiac muscle tissue, they may be modified readily by one ofskill in the art to stimulate drug-eluting cells in accordance with theteachings of the present invention. It will be appreciated that thestimulation device according to the present invention can include a widevariety of microprocessor-based implantable stimulators similar to thoseused in pacemakers, as disclosed in U.S. Pat. No. 5,158,078 (Bennett etal.), U.S. Pat. No. 5,312,453 (Shelton et al.), and U.S. Pat. No.5,144,949 (Olson), and pacemaker/cardioverter/defibrillators (PCDs), asdisclosed in U.S. Pat. No. 5,545,186 (Olson et al.), U.S. Pat. No.5,354,316 (Keimel), U.S. Pat. No. 5,314,430 (Bardy), U.S. Pat. No.5,131,388 (Pless), and U.S. Pat. No. 4,821,723 (Baker et al.).Alternatively, the stimulation device can include stimulating elementssimilar to those used in implantable nerve or muscle stimulators, suchas those disclosed in U.S. Pat. No. 5,199,428 (Obel et al.), U.S. Pat.No. 5,207,218 (Carpentier et al.), and U.S. Pat. No. 5,330,507(Schwartz).

In general, the implantable stimulation device 22 shown in FIG. 2includes a hermetically sealed enclosure that may include variouselements, such as an electrochemical cell (e.g., a lithium battery) forproviding electrical current to circuitry, circuitry that controlsdevice operations, a telemetry transceiver antenna, and a circuit thatreceives downlinked telemetry commands from and transmits stored data ina telemetry uplink to an external programmer, in addition to otherelements.

FIG. 5 is a block diagram illustrating various components of animplantable stimulation device 22 which is programmable by means of anexternal programming unit (not shown). One such programmer easilyadaptable for the purposes of the present invention is the commerciallyavailable Medtronic Model 9790 programmer. The programmer is amicroprocessor device which provides a series of encoded signals tostimulation device 22 by means of a programming head which transmitsradio frequency encoded signals according to a telemetry system, such asthat described in U.S. Pat. No. 5,312,453 (Wyborny et al.), for example.

Stimulation device 22, illustratively shown in FIG. 5 as an exemplaryembodiment, is electrically coupled to lead or antenna 24. Lead 24 maybe used for stimulating only, or it may be used for both stimulating andsensing. Lead 24 is coupled to a node 62 in the circuitry of stimulationdevice 22 through input capacitor 60. Input/output circuit 68 alsocontains circuits for interfacing with stimulation device 22, antenna66, and circuit 74 for application of stimulating signals to lead 24under control of software-implemented algorithms in microcomputer unit78.

Microcomputer unit 78 comprises on-board circuit 80 which includessystem clock 82, microprocessor 83, and on-board RAM 84 and ROM 86. Inthis illustrative embodiment, off-board circuit 88 comprises a RAM/ROMunit. On-board circuit 80 and off-board circuit 88 are each coupled by adata communication bus 90 to digital controller/timer circuit 92. Theelectrical components shown in FIG. 5 are powered by an appropriateimplantable battery power source 94 in accordance with common practicein the art. For purposes of clarity, the coupling of battery power tothe various components of stimulating element 22 is not shown in thefigures.

Antenna 66 is connected to input/output circuit 68 to permituplink/downlink telemetry through RF transmitter and receiver unit 55.Unit 55 may correspond to the telemetry and program logic disclosed inU.S. Pat. No. 4,556,063 (Thompson et al.), or to that disclosed in theabove-referenced Wyborny et al. patent. Voltage reference (V_(REF)) andbias circuit 61 generates a stable voltage reference and bias currentfor the analog circuits of input/output circuit 68. Analog-to-digitalconverter (ADC) and multiplexer unit 58 digitizes analog signals andvoltages to provide “real-time” telemetry signals and batteryend-of-life (EOL) replacement functions.

Sense amplifier 53 amplifies sensed signals and provides an amplifiedsignal to peak sense and threshold measurement circuitry 57. Circuitry57, in turn, provides an indication of peak sensed voltages and measuredsense amplifier threshold voltages on path 64 to digitalcontroller/timer circuit 92. An amplified sense amplifier signal is thenprovided to comparator/threshold detector 59. Sense amplifier 53 maycorrespond in some respects to that disclosed in U.S. Pat. No. 4,379,459(Stein).

Circuit 92 is further preferably coupled to electrogram (EGM) amplifier76 for receiving amplified and processed signals sensed by an electrodedisposed on lead 24. The electrogram signal provided by EGM amplifier 76is employed when the implanted device is being interrogated by anexternal programmer (not shown) to transmit by uplink telemetry arepresentation of an analog electrogram of the patient's electricalheart activity. Such functionality is, for example, shown in previouslyreferenced U.S. Pat. No. 4,556,063. Note that lead or antenna 24 may belocated in positions other than inside the heart.

Output pulse generator 74 provides stimuli to lead 24 through couplingcapacitor 65 in response to a stimulating trigger signal provided bydigital controller/timer circuit 92. Output amplifier 74, for example,may correspond generally to the output amplifier disclosed in U.S. Pat.No. 4,476,868 (Thompson).

It is to be understood that FIG. 5 is an illustration of an exemplarytype of stimulation device which may find application in the presentinvention, or which may be modified for use in the present invention byone of skill in the art, and is not intended to limit the scope of thepresent invention.

In addition to a stimulating element within stimulation device 22,systems of the present invention include a sensing element formonitoring at least one physiological property to detect a change in aphysiological condition (typically, the onset of ischemia caused by adecrease in blood flow due to an occlusion resulting from the rupture ofunstable plaque). For example, a pseudo-surface electrocardiogram (ECG)using a subcutaneous electrode array can be used to detect a reductionin blood flow, which is represented by an abnormal morphology (e.g.,inverted shape) of a T wave (i.e., the portion of an ECG pattern due toventricular repolarization or recovery). Such a pseudo-surface ECG issimilar to a normal ECG modified for implantation. In this sensingelement, for example, an implantable pulse generator having threeelectrodes, each only about one centimeter apart, could be implantedinto the pectoralis muscle in the chest of a patient. An ECG pattern,similar to that of a normal ECG, would be monitored for an indication ofan abnormal morphology of a T wave.

Sensing elements can include one or more individual sensors formonitoring one or more physiological properties. In addition to apseudo-surface ECG, such sensors include, for example, blood gas (e.g.,CO₂) sensors, pH sensors, blood flow sensors in the coronary sinus, andthe like. Other mechanisms of detection that can be used in sensorsinclude, for example, acoustic time of flight changes as a result offlow, acoustic doppler, which takes advantage of the doppler effect(received frequency is different that the transmitted one), thermaldilution (a clinical technique to measure blood flow and cardiacoutput), and venous pressure drop due to lack of driving pressure fromthe blocked artery. Examples of sensors or implantable monitoringdevices that can be modified to be used in the stimulation devices ofthe present invention are disclosed, for example, in U.S. Pat. No.5,409,009 (Olson), U.S. Pat. No. 5,702,427 (Ecker et al.), and U.S. Pat.No. 5,331,966 (Bennet et al.). Suitable sensors and sensing techniquesare well known to one of skill in the art and can be readily adapted foruse in the present invention.

For electrical stimulation, because the direct wiring from thestimulation device to the delivery device is not feasible, a telemetriccommunication system can be used. Such systems are known and can bemodified to be used in the present invention. Examples of such systemsare discussed above and described in U.S. Pat. No. 5,312,453 (Wyborny etal.), for example. Referring again to FIG. 2, the stimulation device 22will produce a radio frequency (RF) signal 26 using lead 24 as atransmitting antenna, which is implanted into the right ventricle of apatient's heart. The lead 24 includes a coil, which transmits an H-fieldcoupled pulse series (e.g., a 175 kilocycle, pulse position modulated,H-field signal) to the coil formed by stent 18, which is implanted intothe left ventricle of a patient's heart. For a conversion of themagnetic field (H-field) into an electrical signal, the stent includes ametal coil with all but the ends coated with an insulating coating. Atuned LC filter integral with the stent 18 will receive some of thissignal, rectify it, and when a sufficient charge is transferred from thestimulation device to the stent, energy will be used to electricallystimulate the engineered endothelial cells in the coronary artery totrigger the release of the therapeutic agent. Inset FIG. 2A is arepresentation of a circuit within the stent. This circuit includes anLC filter tuned to the specific frequency of the RF signal 26 forinduction of electric current in the coiled stent 18 (or in a coilprovided in the stent). A charge is stored in capacitor (C_(storage))until a threshold voltage is reached, which activates a switch to closethe circuit and cause current to flow through the cells associated withthe stent. In such a system, the current density produced is preferablysufficient to stimulate the cells to release a therapeutic agent withoutsignificant damage to the cells or the therapeutic agents. Based on invitro experiments, the current density for preferred embodiments ismaintained below about 540 μ-Amp/mm² and the current threshold belowabout 0.9 mA/mm² to avoid damage to the endothelial cells or theexpressed product.

Thus, the delivery device that acts as a carrier for the drug-elutingcells can be powered with RF coupling. Alternatively, it can be selfpowered or battery powered.

EXAMPLES

The following examples are intended for illustration purposes only.

Electrical Stimulation Studies

Electrical and mechanical hardware were modified to enable thestimulation of endothelial cells cultured on inserts placed in tissueculture wells. The cells were stimulated with single pulses (1millisecond long and delivered at a rate of 1 Hz) for 5 minutes a day,on 3 consecutive days. At the end of the 3 days, cells were removed fromthe culture wells, stained with crystal violet and photographed.Increases in the current density caused a decrease in the density of redstained endothelial cells. While a stimulation pattern that produced 540μ-Amp/mm² of current density appears to be detrimental to theendothelial cells, another pattern which produced 270 μ-Amp/mm² ofcurrent density did not.

Studies continued to determine the stimulation parameters, and upperlimits on the current density to prevent cell damage. By modifying theinterface circuit between the stimulator and the tissue culture wells,the current densities in wells where endothelial cell cultures weregrown were monitored. Below is a table summarizing the data.

Current Current Current Density Density Density Well Day 1 Day 2 Day 3Number (mA/mm²) (mA/mm²) (mA/mm²) Observations A1 2.10 1.99 PULLED Zoneof death on the near OUT edge of the well closest to the outsideelectrode A2 1.66 1.55 PULLED Zone of death on the near OUT edge of thewell closest to the outside electrode A3 1.77 1.66 PULLED Zone of deathon the near OUT edge of the well closest to the outside electrode A40.99 0.99 PULLED Some floating cells, OUT No significant cell death nearoutside electrode A5 0.88 0.88 PULLED Some floating cells, OUT Nosigniflcant cell death near outside electrode A6 0.00 0.00 PULLED Somefloating cells, OUT Cells appear to be healthy B1 2.10 2.21 2.24 Zone ofdeath on the near edge of the well closest to the outside electrode B21.35 1.33 1.55 Zone of death on the near edge of the well closest to theoutside electrode B3 1.55 1.77 1.88 Zone of death on the near edge ofthe well closest to the outside electrode B4 0.84 0.88 1.11 Starting tosee cell death around the edge of the well closest to the outsideelectrode B5 0.84 0.88 0.94 Starting to see cell death around the edgeof the well closest to the outside electrode B6 0.00 0.00 0.00 Somefloating cells, Cells appear to be healthy

By looking at the data shown above, 0.9-1.0 mA/mm² appears to be thecurrent threshold for damaging the endothelial cells with in vitroelectrical stimulation.

Example 1

Cell Culture Studies

Human coronary artery endothelial cells (Clonetics, San Diego, Calif.)were seeded in 24 well tissue culture plates at 1×10⁴ cells/cm² (1.5 mLtotal volume) and grown in defined media as supplied by Clonetics. Thecells were incubated at 37° C., 5% CO₂ for up to four days. The mediawas not changed on the cells during the course of the experiment.Supernatants from duplicate wells were withdrawn on days 2, 3, and 4post-seeding. In addition, cells plus supernatants from a second set ofsamples were harvested from duplicate wells on days 2, 3, and 4post-seeding. Samples were stored at −85° C. until assayed. The ELISAassay was performed on the test samples and on controls following theprocedure outlined by the manufacturer (American Diagnostica, Inc.) Thestandard curve was generated using control plasma A, t-PA antigencontrol plasma set 2 (Product #275, American Diagnostica, Inc.). Thetest samples were assayed undiluted (20 μL assay volume). The resultssuggest that measurable t-PA was released from control endothelialcells, in the absence of stimulation. The levels of t-PA that werereleased were correlated to cell growth (more was measured after 4 daysof culture than after 2 days).

Example 2

Cell Culture Studies

This experiment was performed similarly to the first experiment with thefollowing changes. In the first part of the experiment, cells wereseeded at three different densities (1×10⁴, 2×10⁴, 4×10⁴) in 0.5 mLtotal volume per well, and the cell supernatants were collected on day 2and day 3 post seeding. In the second part of the experiment, cells wereseeded at 2×10⁴ cells/cm² and one group was stimulated once (on day 2post seeding) and a second group was stimulated two times (once on day 2and once on day 3 post seeding). The stimulation level was 55V (350-440mA) for 5 minutes and supernatants were collected 15 minutes afterstimulation. The following tables contain the data that was obtainedfrom this experiment. The data confirms what was observed in the firstexperiment—that t-PA production/release is correlated with cell numberand with cell growth. Although this data from the stimulated samplessuggests that electrical stimulation at 55 volts for 5 minutes did notincrease t-PA production/release as compared to the unstimulatedcontrol, it did not cause adverse effects on the released t-PA.

Density Day 2 Day 3 st dev std 1 × 10⁴ 15.153 23.208 0.088 1.73  2 × 10⁴33.164 41.219 5.9  1.566 4 × 10⁴ 44.773 54.926 3.309 1.755 Condition Day1 Day 2 stdev std No Stim 8.581 12.447 0.366 0.278 1× Stim 8.08  10.86 0.54  0.176 2× Stim 11.264 0.663

The complete disclosures of the patents, patent applications, andpublications listed herein are incorporated by reference, as if eachwere individually incorporated by reference. The above examples anddisclosure are intended to be illustrative and not exhaustive. Theseexamples and description will suggest many variations and alternativesto one of ordinary skill in this art. All these alternatives andvariations are intended to be included within the scope of the attachedclaims. Those familiar with the art may recognize other equivalents tothe specific embodiments described herein which equivalents are alsointended to be encompassed by the claims attached hereto.

What is claimed is:
 1. An implantable system comprising: (a) a deliverydevice comprising a carrier and eukaryotic cells that produce at leastone therapeutic agent; (b) a stimulating element operatively coupled tothe delivery device for stimulating the release of the therapeutic agentfrom the delivery device; and (c) a sensing element for monitoring atleast one physiological property of a patient in which the system isimplanted and communicating with the stimulating element to stimulatethe release of the therapeutic agent from the delivery device.
 2. Theimplantable system of claim 1 wherein the carrier is selected from agroup consisting of stents, vascular grafts, stent grafts, syntheticpatches, infusion sleeves, medical electrical leads, medical electricalelectrodes, and indwelling catheters.
 3. The implantable system of claim2 wherein the delivery device comprises: (a) an intraluminal stentcomprising: (i) a lumen-wall contacting surface; (ii) a lumen-exposedsurface; (iii) a polymer composition covering at least a portion of thestent; and (b) eukaryotic cells residing with the first polymercomposition.
 4. The implantable system of claim 3 wherein the firstpolymer composition is capable of dehydration and rehydration.
 5. Theimplantable system of claim 3 wherein the polymer composition isselected from a group consisting of fibrins, collagens, alginates,polylactic acids, polyglycolic acids, celluloses, hyaluronic acids,polyurethanes, silicones, polycarbonates, mixtures and copolymersthereof.
 6. The implantable system of claim 1 wherein the eukaryoticcells are selected from a group consisting of endothelial cells,fibroblasts, and mixtures thereof.
 7. The implantable system of claim 6wherein the eukaryotic cells comprise endothelial cells.
 8. Theimplantable system of claim 7 wherein the endothelial cells areautologous.
 9. The implantable system of claim 7 wherein the endothelialcells are genetically engineered.
 10. The implantable system of claim 1wherein the therapeutic agent is selected from a group consisting ofanticoagulant agents, antiplatelet agents, antifibrinolytic agents,angiogenesis factors, and mixtures thereof.
 11. The implantable systemof claim 1 wherein the therapeutic agent is selected from a groupconsisting of activated protein C, tissue plasminogen activator,prostacyclin, and vascular endothelial growth factor.
 12. Theimplantable system of claim 1 wherein the delivery device furthercomprises a containment vehicle in which the cells are located.
 13. Theimplantable system of claim 1 wherein the stimulating element comprisesan implantable pulse generator.
 14. The implantable system of claim 1wherein the stimulating element is selected from a group consisting ofan electrical stimulating element, a mechanical stimulating element, anacoustic stimulating element, a chemical stimulating element, a thermalstimulating element, and combinations thereof.
 15. The implantablesystem of claim 14 wherein the stimulating element is an electricalstimulating element.
 16. The implantable system of claim 1 wherein thesensing element comprises at least one sensor.
 17. The implantablesystem of claim 1 wherein the sensing element comprises a pseudo-surfaceelectrocardiogram using a subcutaneous electrode array for detecting areduction in blood flow.
 18. The implantable system of claim 1 whereinthe sensing element is selected from a group consisting of a blood gassensor, a pH sensor, and a blood flow sensor.
 19. A method of localdelivery of a therapeutic agent to a patient, the method comprising: (a)providing an implantable system comprising: (i) a delivery devicecomprising a carrier and eukaryotic cells that produce at least onetherapeutic agent; (ii) a stimulating element operatively coupled to thedelivery device for stimulating the release of the therapeutic agentfrom the delivery device; and (iii) a sensing element for monitoring atleast one physiological property of a patient in which the system isimplanted and communicating with the stimulating element to stimulatethe release of the therapeutic agent from the delivery device; and (b)implanting the implantable system into the body of a patient; whereinthe therapeutic agent is released from the delivery device when thesensing element detects a predetermined level of a physiologicalproperty and communicates with the stimulating element to trigger therelease of the therapeutic agent.
 20. The method of claim 19 wherein thestimulating element stimulates the cells to release the therapeuticagent.
 21. The method of claim 19 wherein the delivery device furthercomprises a containment vehicle in which the cells are located.
 22. Themethod of claim 21 wherein the stimulating element stimulates thecontainment vehicle to release the therapeutic agent.
 23. The method ofclaim 21 wherein the stimulating element is selected from a groupconsisting of an electrical stimulating element, a mechanicalstimulating element, an acoustic stimulating element, a chemicalstimulating element, and a thermal stimulating element.
 24. The methodof claim 23 wherein the stimulating element electrically stimulates thecells to release the therapeutic agent.
 25. The method of claim 19wherein the sensing element comprises at least one sensor.
 26. Themethod of claim 19 wherein the sensing element is selected from a groupconsisting of a blood gas sensor, a pH sensor, and a blood flow sensor.27. An implantable system comprising: (a) a delivery device comprisingan intraluminal stent carrier having a lumen-wall contacting surface anda lumen-exposed surface, a polymer composition covering at least aportion of the stent carrier, and eukaryotic cells residing with thepolymer composition and being adapted to produce at least onetherapeutic agent; (b) a stimulating element operatively coupled to thedelivery device for stimulating (b) a stimulating element operativelycoupled to the delivery device for stimulating the release of thetherapeutic agent from the delivery device; and (c) a sensing elementfor monitoring at least one physiological property of a patient in whichthe system is implanted and communicating with the stimulating elementto stimulate the release of the therapeutic agent from the deliverydevice.
 28. The implantable system of claim 27 wherein the polymercomposition is selected from a group consisting of fibrins, collagens,alginates, polylactic acids, polyglycolic acids, celluloses, hyaluronicacids, polyurethanes, silicones, and polycarbonates.
 29. The implantablesystem of claim 27 wherein the therapeutic agent is selected from agroup consisting of anticoagulant agents, antiplatelet agents,antifibrinolytic agents, angiogenesis factors, activated protein C,tissue plasminogen activator, prostacyclin, and vascular endothelialgrowth factor.
 30. The implantable system of claim 27 wherein thesensing element is selected from a group consisting of a blood gassensor, a pH sensor, and a blood flow sensor.
 31. The implantable systemof claim 27 wherein the stimulating element comprises an implantablepulse generator.
 32. The implantable system of claim 27 wherein thestimulating element delivers an electrical signal to cause release ofthe therapeutic agent.
 33. A method of local delivery of a therapeuticagent to a patient, the method comprising: (a) providing an implantablesystem comprising: (i) a delivery device comprising a carrier andeukaryotic cells that produce at least one therapeutic agent; (ii) astimulating element operatively coupled to the delivery device forstimulating the release of the therapeutic agent from the deliverydevice; and (iii) a sensing element for monitoring at least onephysiological property of a patient in which the system is implanted andcommunicating with the stimulating element to stimulate the release ofthe therapeutic agent from the delivery device; and (b) implanting theimplantable system into the body of a patient; wherein the therapeuticagent is released from the delivery device when the sensing elementdetects a predetermined level of a physiological property andcommunicates with the stimulating element to trigger the release of thetherapeutic agent and wherein the sensing element is selected from agroup consisting of a blood gas sensor, a pH sensor, and a blood flowsensor.
 34. The method of claim 33 wherein the stimulating elementdelivers an electrical signal to cause release of the therapeutic agent.35. The method of claim 34 wherein the stimulating element comprises animplantable pulse generator.
 36. The method of claim 33 wherein thedelivery device comprises an intraluminal stent.
 37. The method of claim33 wherein the delivery device is selected from a group consisting ofstents, vascular grafts, stent grafts, synthetic patches, infusionsleeves, and indwelling catheters.